ABSTRACT Pulmonary arterial hypertension (PAH), a disease of the small pulmonary arteries, is characterized by pulmonary vasoconstriction, vascular cell proliferation, and vascular remodeling leading to right ventricular hypertrophy and failure. Despite advances in understanding and treatment, disease management and prognosis remain grim. Current therapies for PAH focus on restoring proper vascular tone via vasodilatory mechanisms. However, these therapies fall short and do not reverse patient outcome. Therefore, there is a critical need to better understand and address the mechanisms underlying cellular remodeling and subsequent reduction of luminal area in pulmonary arteries that lead to increased vascular resistance. In cases of heritable disease with familial origin, mutations in the bone morphogenetic protein receptor 2 (BMPR2) predispose individuals to development of PAH. Recent studies show an increase in TGF?-1 levels and signaling in PAH, and BMPR2 mutations may lead to increased TGF? signaling. Increases in TGF? signaling associated with decreased BMPR2 expression can promote cellular reprogramming and vascular remodeling. Evidence implicates the FK506-binding protein 51 (FKBP51) as a major regulator of cellular remodeling in metastatic melanoma and other cancers. Additionally, TGF?-1, known as a major player in cellular transdifferentiation, stimulates cellular reprogramming in pulmonary artery endothelial cells (PAECs), and a cooperative relationship between TGF? and FKBP51 has been shown in malignant cell progression. Our preliminary work indicates increased expression of FKBP51 in PAECs in a rat model of PAH. Additionally, treatment of PAECs with TGF?-1 increased FKBP51 levels compared to vehicle-treated cells. Overexpression of FKBP51 in PAECs led to an increase in secretion of TGF?. Finally, in BMPR2-deficient PAECs, FKBP51 and ?-smooth muscle actin protein levels were elevated in comparison to control cells. We hypothesize that in PAECs of PAH, and notably in cases of BMPR2 deficiency, FKBP51 is upregulated, increasing TGF? in a positive-feedback loop, resulting in the hallmark pro-proliferative, anti-apoptotic phenotype of PAH. The hypothesis will be tested with three research-specific aims, developed to encourage and engage medical students in the studies. Specific aim 1 will confirm preliminary data that FKBP51 is upregulated in PAH, expand the investigation of FKBP51 expression into females, and characterize the expression of FKBP51 in PAECs in response to TGF?. Specific aim 2 will determine whether FKBP51 induces vascular remodeling in PAH using both animal (male and female) and cellular models. Specific aim 3 will investigate the relationship of TGF?, FKBP51, and other inflammatory signaling molecules such as NF?B. Specific Aim 4 outlines the training plan for student involvement in this research.